title: Discovery and SAR of novel 4-thiazolyl-2-phenylaminopyrimidines as potent inhibitors of spleen tyrosine kinase (SYK).
abstract: A series of SYK inhibitors based on the phenylamino pyrimidine thiazole lead 4 were prepared and evaluated for biological activity. Lead optimization provided compounds with nanomolar K(i)'s against SYK and potent inhibition in mast cell degranulation assays.
authors.affiliation: Department of Medicinal Chemistry, Vertex Pharmaceuticals, Inc., 130 Waverly Street, Cambridge, MA 02139, USA. luc_farmer@vrtx.com
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Farmer
authors.forename: Guy
authors.initials: G
authors.lastname: Bemis
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Britt
authors.forename: John
authors.initials: J
authors.lastname: Cochran
authors.forename: Martin
authors.initials: M
authors.lastname: Connors
authors.forename: Edmund M
authors.initials: EM
authors.lastname: Harrington
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoock
authors.forename: William
authors.initials: W
authors.lastname: Markland
authors.forename: Suganthini
authors.initials: S
authors.lastname: Nanthakumar
authors.forename: Paul
authors.initials: P
authors.lastname: Taslimi
authors.forename: Ernst
authors.initials: E
authors.lastname: Ter Haar
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Darshana
authors.initials: D
authors.lastname: Zhaveri
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008407:Mast Cells / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects; D008968:Molecular Conformation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013154:Spleen / Q000201:enzymology*; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat